The human endogenous retrovirus type K (HERV-K), present at about fifty copies in the genome, appears to be a complete retrovirus with open reading frames encoding gag, pol, and env proteins and a central open reading frame encoding a putative regulatory protein. We have been investigating a possible association of HERV-K with human breast cancer largely due to its homology with mouse mammary tumor virus which causes mammary cancer in mice. Initially, we investigated patient sera for antibodies to HERV-K gag and envelope antigens in peptide-based enzyme- linked immunosorbent assays. Although the number of subjects was small, we found that several patients with highly aggressive inflammatory breast cancer were antibody positive whereas little seroreactivity was seen in sera of normal women or men. We also observed antibodies in sera of Tunisian breast cancer patients. Notably, the Tunisian breast cancer cases were very aggressive, with features resembling inflammatory breast cancer. Tunisian women with benign breast disease were also antibody positive, however, suggesting perhaps that HERV-K expression might be associated with the hormonal environment rather than with disease. Antibodies were not prevalent in several familial breast cancer patients, from whom sera had been obtained long after treatment. A higher prevalence was observed in sera of relatives of familial breast cancer patients. These preliminary findings suggested that a subset of breast cancers, namely inflammatory breast cancer, might be associated with HERV-K expression. To pursue this idea, we carried out a study on breast cancer aggressiveness as related to HERV- K seropositivity. The results were inconclusive, as we found that seropositivity was influenced by the time of sera collection. HERV-K reactivity tended to be greater when sera were obtained from women prior to treatment, compared to sera obtained post-therapy. We are currently evaluating sera of untreated breast cancer cases and expanding the study to examine larger numbers of sera from normal women. In addition, analysis of a large group of Tunisian breast cancer and benign breast disease sera obtained at the time of diagnosis is on- going in an attempt to confirm the earlier suggestive results. The results should clarify whether the endogenous virus is associated with the inflammatory breast cancer subtype, and might lead to development of simple diagnostic tests. - breast cancer, DNA methylation, endogenous retroviruses, etiology, mRNA expression, seroepidemiology, - Human Tissues, Fluids, Cells, etc.